PMID- 26083030
OWN - NLM
STAT- MEDLINE
DCOM- 20160428
LR  - 20181113
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 6
DP  - 2015
TI  - Apolipoprotein D Transgenic Mice Develop Hepatic Steatosis through Activation of 
      PPARgamma and Fatty Acid Uptake.
PG  - e0130230
LID - 10.1371/journal.pone.0130230 [doi]
LID - e0130230
AB  - Transgenic mice (Tg) overexpressing human apolipoprotein D (H-apoD) in the brain 
      are resistant to neurodegeneration. Despite the use of a neuron-specific promoter 
      to generate the Tg mice, they expressed significant levels of H-apoD in both 
      plasma and liver and they slowly develop hepatic steatosis and insulin 
      resistance. We show here that hepatic PPARgamma expression in Tg mice is increased by 
      2-fold compared to wild type (WT) mice. Consequently, PPARgamma target genes Plin2 
      and Cide A/C are overexpressed, leading to increased lipid droplets formation. 
      Expression of the fatty acid transporter CD36, another PPARgamma target, is also 
      increased in Tg mice associated with elevated fatty acid uptake as measured in 
      primary hepatocytes. Elevated expression of AMPK in the liver of Tg leads to 
      phosphorylation of acetyl CoA carboxylase, indicating a decreased activity of the 
      enzyme. Fatty acid synthase expression is also induced but the hepatic 
      lipogenesis measured in vivo is not significantly different between WT and Tg 
      mice. In addition, expression of carnitine palmitoyl transferase 1, the 
      rate-limiting enzyme of beta-oxidation, is slightly upregulated. Finally, we show 
      that overexpressing H-apoD in HepG2 cells in presence of arachidonic acid (AA), 
      the main apoD ligand, increases the transcriptional activity of PPARgamma. Supporting 
      the role of apoD in AA transport, we observed enrichment in hepatic AA and a 
      decrease in plasmatic AA concentration. Taken together, our results demonstrate 
      that the hepatic steatosis observed in apoD Tg mice is a consequence of increased 
      PPARgamma transcriptional activity by AA leading to increased fatty acid uptake by 
      the liver.
FAU - Labrie, Marilyne
AU  - Labrie M
AD  - Centre de recherche BioMed, Departement des Sciences Biologiques, Universite du 
      Quebec, Montreal, Quebec, H3C 3P8, Canada.
FAU - Lalonde, Simon
AU  - Lalonde S
AD  - Centre de recherche BioMed, Departement des Sciences Biologiques, Universite du 
      Quebec, Montreal, Quebec, H3C 3P8, Canada.
FAU - Najyb, Ouafa
AU  - Najyb O
AD  - Centre de recherche BioMed, Departement des Sciences Biologiques, Universite du 
      Quebec, Montreal, Quebec, H3C 3P8, Canada.
FAU - Thiery, Maxime
AU  - Thiery M
AD  - Centre de recherche BioMed, Departement des Sciences Biologiques, Universite du 
      Quebec, Montreal, Quebec, H3C 3P8, Canada.
FAU - Daneault, Caroline
AU  - Daneault C
AD  - Montreal Heart Institute Research Center, Montreal, Quebec, H1T 1C8,Canada.
FAU - Des Rosiers, Chrisitne
AU  - Des Rosiers C
AD  - Department of Nutrition, Universite de Montreal, Montreal, Quebec, H3C 
      3J7,Canada; Montreal Heart Institute Research Center, Montreal, Quebec, H1T 
      1C8,Canada.
FAU - Rassart, Eric
AU  - Rassart E
AD  - Centre de recherche BioMed, Departement des Sciences Biologiques, Universite du 
      Quebec, Montreal, Quebec, H3C 3P8, Canada.
FAU - Mounier, Catherine
AU  - Mounier C
AD  - Centre de recherche BioMed, Departement des Sciences Biologiques, Universite du 
      Quebec, Montreal, Quebec, H3C 3P8, Canada.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150617
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (APOD protein, human)
RN  - 0 (Apolipoproteins D)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (CCAAT-Enhancer-Binding Proteins)
RN  - 0 (CD36 Antigens)
RN  - 0 (Cidea protein, mouse)
RN  - 0 (Fatty Acids)
RN  - 0 (Membrane Proteins)
RN  - 0 (PLIN2 protein, human)
RN  - 0 (PPAR gamma)
RN  - 0 (Perilipin-2)
RN  - 0 (Plin2 protein, mouse)
RN  - 0 (Proteins)
RN  - 0 (fat-specific protein 27, mouse)
RN  - 27YG812J1I (Arachidonic Acid)
RN  - EC 2.3.1.85 (Fatty Acid Synthases)
SB  - IM
MH  - Animals
MH  - Apolipoproteins D/*genetics
MH  - Apoptosis Regulatory Proteins/metabolism
MH  - Arachidonic Acid/blood/metabolism/pharmacology
MH  - CCAAT-Enhancer-Binding Proteins/genetics
MH  - CD36 Antigens/metabolism
MH  - Fatty Acid Synthases/metabolism
MH  - Fatty Acids/*metabolism
MH  - Fatty Liver/*genetics/*metabolism
MH  - Gene Expression Regulation/drug effects
MH  - Hep G2 Cells
MH  - Humans
MH  - Lipid Droplets/drug effects/metabolism
MH  - Lipogenesis/drug effects
MH  - Liver/drug effects/metabolism
MH  - Male
MH  - Membrane Proteins/metabolism
MH  - Mice
MH  - Mice, Transgenic
MH  - PPAR gamma/genetics/*metabolism
MH  - Perilipin-2
MH  - Protein Transport/drug effects
MH  - Proteins/metabolism
PMC - PMC4470830
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2015/06/18 06:00
MHDA- 2016/04/29 06:00
PMCR- 2015/06/17
CRDT- 2015/06/18 06:00
PHST- 2014/12/03 00:00 [received]
PHST- 2015/05/18 00:00 [accepted]
PHST- 2015/06/18 06:00 [entrez]
PHST- 2015/06/18 06:00 [pubmed]
PHST- 2016/04/29 06:00 [medline]
PHST- 2015/06/17 00:00 [pmc-release]
AID - PONE-D-14-54236 [pii]
AID - 10.1371/journal.pone.0130230 [doi]
PST - epublish
SO  - PLoS One. 2015 Jun 17;10(6):e0130230. doi: 10.1371/journal.pone.0130230. 
      eCollection 2015.